Cardiodepressant actions of the orally active male contraceptive, gossypol, in guinea-pig heart muscle.

We have previously shown that gossypol has direct actions on isolated atrial muscle preparations. The possible mechanisms responsible for the transient positive and sustained negative inotropic effects of gossypol were examined under conditions that modify Ca2+ pools involved in contractile activation. In Langendorff preparations obtained from guinea-pig or rat heart, gossypol produced marked negative inotropic and arrhythmogenic effects but failed to produce a positive inotropic effect. Langendorff preparations were significantly more sensitive than atrial muscle preparations. In atrial muscle preparations, the negative inotropic effect of gossypol was not specific to utilization of superficial or intracellular Ca2+ pools; force-staircase phenomenon observed between 0.5 and 3 Hz, contractions elicited by slow action potentials in partially depolarized muscle, the inotropic effect of extracellular Ca2+ and potentiated post-rest contractions were all suppressed by gossypol to the similar extent. Low external Na+ concentrations abolished the positive inotropic effect of gossypol without affecting the negative inotropic effect. A low extracellular Ca2+ concentration enhanced the transient positive inotropic effect and delayed development of the negative inotropic effect. Simultaneous reduction of extracellular Na+ and Ca2+ concentrations abolished the positive inotropic effect and enhanced the negative inotropic effect. Gossypol inhibited ATP-dependent Ca2+ uptake by sarcolemmal vesicles obtained from dog heart. These results indicate that the actions of gossypol on cardiac muscle is not specific to utilization of either the superficial or intracellular Ca2+ pools involved in contractile activation.